223

Hypertens Res
Vol.28 (2005) No.3
p.223

Original Article

Interaction between Amlodipine and Simvastatin in

Patients with Hypercholesterolemia and Hypertension
Shinichiro NISHIO, Hiroshi WATANABE, Kazuhiro KOSUGE, Shinya UCHIDA,
Hideharu HAYASHI*, and Kyoichi OHASHI

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are often prescribed in association

with antihypertensive agents, including calcium antagonists. Simvastatin is an HMG-CoA reductase inhibitor
that is metabolized by the cytochrome P450 (CYP) 3A4. The calcium antagonist amlodipine is also metabo-
lized by CYP3A4. The purpose of this study was to investigate drug interactions between amlodipine and
simvastatin. Eight patients with hypercholesterolemia and hypertension were enrolled. They were given 4
weeks of oral simvastatin (5 mg/day), followed by 4 weeks of oral amlodipine (5 mg/day) co-administered
with simvastatin (5 mg/day). Combined treatment with simvastatin and amlodipine increased the peak con-
centration (Cmax) of HMG-CoA reductase inhibitors from 9.6 ± 3.7 ng/ml to 13.7 ± 4.7 ng/ml (p < 0.05) and the
area under the concentration-time curve (AUC) from 34.3 ± 16.5 ng h/ml to 43.9 ± 16.6 ng h/ml (p < 0.05) with-
out affecting the cholesterol-lowering effect of simvastatin. This study is the first to determine prospectively
the pharmacokinetic and pharmacodynamic interaction between amlodipine and simvastatin. (Hypertens
Res 2005; 28: 223–227)

Key Words: drug interaction, simvastatin, amlodipine, hypercholesterolemia

ylene (10−12). The pharmacokinetics of simvastatin has been

reported to be affected by potent CYP3A4 inhibitors such as
Introduction
itraconazole (13), erythromycin (14), verapamil (14) and
Control of hypercholesterolemia is important for the preven- nelfinavir (15). Moreover, we have previously reported that
tion of coronary artery disease (CAD) (1−5). Currently, 3- diltiazem, which is a selective inhibitor of CYP3A4 (16, 17),
hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reduc- caused a 2-fold increase of the area under the concentration-
tase inhibitors are the first-choice therapeutic agents for time curve (AUC) of HMG-CoA reductase inhibitors (18).
patients with hypercholesterolemia (6−8). The HMG-CoA Hypercholesterolemia is often accompanied by hyperten-
reductase inhibitor simvastatin is widely used and has been sion, an associated risk factor for CAD (19−21). Calcium
shown to reduce morbidity and mortality from CAD (9). Sim- antagonists have been widely used in the treatment of hyper-
vastatin is an inactive lactone pro-drug that is hydrolyzed by tension and/or angina pectoris (22−26), and are often pre-
esterases to simvastatin acid, the active competitive inhibitor scribed in association with a lipid-lowering agent such as
of HMG-CoA reductase (10−12). Simvastatin and simvasta- simvastatin. Amlodipine is one of the 1,4-dihydropyridine
tin acid are mainly metabolized by the cytochrome P450 calcium antagonists with a long elimination half-life (27−29).
(CYP) 3A4 to 3′,5′-dihydrodiol, 3′-hydroxy and 6′-exometh- Amlodipine undergoes the oxidative metabolism of dihydro-

From the Department of Clinical Pharmacology and Therapeutics and *Department of Internal Medicine III, Hamamatsu University School of Medicine,
Hamamatsu, Japan.
This study was supported by a Grant for Comprehensive Research on Aging and Health (H16-choju-001) from the Ministry of Health, Labor and Wel-
fare of Japan.
Address for Reprints: Shinichiro Nishio, M.D., Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1−
20−1 Handayama, Hamamatsu 431−3192, Japan. E-mail: shinn@hama-med.ac.jp
Received October 25, 2004; Accepted in revised form December 21, 2004.
224 Hypertens Res Vol. 28, No. 3 (2005)

Table 1. Patient Demographics and Basic Medical Data

Age (years old) 64.1±6.0
Sex (male/female) 5/3
Body weight (kg) 61.5±5.9
Total cholesterol (mg/dl) 253±31
LDL-cholesterol (mg/dl) 164±26
HDL-cholesterol (mg/dl) 54±9
Triglyceride (mg/dl) 179±95
Values are mean±SD. LDL, low-density lipoprotein; HDL,
high-density lipoprotein.

pyridine to a pyridine analogue by CYP3A4 (30). In an in-

vitro study, amlodipine was shown to have strong inhibitory
effects on CYP1A1, CYP2B6 and CYP2C9, and a weak Fig. 1. Time profiles of the mean plasma concentrations of
inhibitory effect on CYP3A4 when using microsomes from HMG-CoA reductase inhibitors on the last day of 4 weeks of
human B-lymphoblast cells expressing CYP (31). Although treatment with simvastatin (5 mg/day) or combined treatment
amlodipine is one of the most frequently used calcium antag- with simvastatin (5 mg/day) and amlodipine (5 mg/day).
onists, the drug interaction between amlodipine and substrate Each point represents the mean ± SD.
drugs for CYP3A4 has not been clinically investigated. In this
study we prospectively studied the pharmacokinetic and phar-
macodynamic drug interaction between amlodipine and sim- trial periods. After an overnight fast, a pre-dosing venous
vastatin in patients with hypercholesterolemia and blood sample was taken, which was used to measure serum
hypertension. total cholesterol (TC), high-density lipoprotein cholesterol
(HDL-C) and triglyceride (TG) enzymatically, and the low-
density lipoprotein cholesterol (LDL-C) concentration was
Methods
calculated according to the Friedewald formula method (32).
All patients drank a glass of water after swallowing the tab-
Subjects
lets. Blood samples were then taken 2, 3, 4 and 6 h after sim-
Eight patients with mild hypertension and hypercholester- vastatin administration. A standardized breakfast and lunch
olemia who had been treated with simvastatin (5 mg/day) and were served 2 and 4 h after drug intake. Plasma was separated
the angiotensin-converting enzyme inhibitor enalapril (5 mg/ within 30 min and stored at - 70°C until analysis.
day) for more than 3 months were enrolled. Before the start of
any antihypertensive therapy, the mean systolic and diastolic
Determination of Simvastatin HMG-CoA Reduc-
blood pressure levels (SBP/DBP) were 151 ±29 mmHg and
tase Inhibitor Concentrations
88±11 mmHg, respectively. The patient demographics and
basic medical data are shown in Table 1. Patients had no his- Plasma concentrations of HMG-CoA reductase inhibitors
tory of hepatic or renal disease. The study protocol was were determined as previously described (33). An equal vol-
approved by the Ethical Committee of Hamamatsu University ume of methanol was added to the plasma samples and the
School of Medicine. All subjects gave written informed con- mixtures were vortexed thoroughly, kept on ice for 10 min,
sent before participating in the study. and centrifuged. Fifty microliters of the supernatants were
dried in an evaporator (SpeedVac; Savant Instruments, Farm-
ingdale, USA). The reaction mixture (96 μl) was added
Study Design
directly to the dried residues to make a final volume of 100 μl
This was a two-phase fixed-order design study. In the first containing 0.1 mol/l KPO4 (pH 7.4), 10 mmol/l 1,4-dithio-
period, patients were administered oral simvastatin (5 mg/ threitol (DTT), 0.2 mmol/l NADH+ (made fresh daily), 5
day) alone for 4 weeks. In the second period, patients were mmol/l glucose-6-phosphate, 1.4 U/ml glucose-6-phosphate
co-administered amlodipine (5 mg/day) and simvastatin (5 dehydrogenase and 1 mg/ml bovine serum albumin. The reac-
mg/day) for 4 weeks. No drug other than simvastatin and tion mixture was incubated for 5 min at 37°C, and soluble rat
amlodipine was taken during the study period. liver HMG-CoA reductase was added to 2 μl buffer A: 0.04
mol/l KPO4 (pH 7.4), 0.05 mol/l KCl, 0.1 mol/l sucrose, 0.03
mol/l ethylenediaminetetraacetic acid (EDTA) and 0.01 mol/
Blood Sampling
l DTT (added immediately before use). The mixture was incu-
Blood samples were obtained on the last day of each of the bated at 37°C for 5 min in the presence of the inhibitor-con-
 Nishio et al: Interaction between Amlodipine and Simvastatin 225

Table 2. Pharmacokinetic Parameters of Simvastatin HMG-CoA Reductase Inhibitor Concentrations

Cmax (ng/ml) t1/2 (h) AUC(0−∞) (ng h/ml)
Simvastatin 9.6±3.7 2.08±0.59 34.3±16.5
Simvastatin + amlodipine 13.7±4.7* 1.97±0.61 43.9±16.6*
Values are mean±SD. Cmax, maximal measured concentration; t1/2, the elimination half-life; AUC(0−∞), area under the concentration-
time curve. *p<0.05 vs. simvastatin monotherapy.

taining plasma sample. The reaction was started with 2 μl of after oral simvastatin dosing with or without amlodipine are
l.25 mg/ml HMG-CoA containing 17.5 μCi/ml glutaryl-3- shown in Fig. 1, and pharmacokinetic parameters of simva-
[14C]HMG-CoA. After an additional 6-min incubation at statin are shown in Table 2. Co-administration of amlodipine
37°C, 20 μl of 5 mol/l HCl was added to lactonize the meva- with simvastatin significantly increased the Cmax and AUC(0−
lonic acid formed. After 15 min, 3.5 ml of a 1:1 suspension of ∞) of HMG-CoA reductase inhibitors to 1.4- and 1.3-fold,
BioRad AG 1 × 8 resin (200−400 mesh) was added and the respectively, in simvastatin monotherapy, but did not affect
tubes (13 × 100) were thoroughly vortexed. [14C]Mevalono- the t1/2 and Tmax of HMG-CoA reductase inhibitors.
lactone was filtered from the resin suspension through poly-
styrene filters (pore size 70 μm; EverGreen, Los Angeles,
Pharmacodynamics
USA) into scintillation vials containing 15 ml of Aquasol-2
(New England Nuclear, Newton, USA) and counted on a Lipid profile, including TC, LDL-C, HDL-C, and TG during
scintillation counter. The percentage of inhibition was con- simvastatin monotherapy and combined treatment with sim-
verted to the inhibitor concentration using a standard curve vastatin and amlodipine, are shown in Fig. 2. There were no
constructed by extracting from the control plasma containing significant differences in lipid profiles between the two peri-
known amounts of L-654, 969, the free acid form of simvasta- ods.
tin. The results were expressed as nanograms of inhibitor per The SBP and DBP values are shown in Table 3. Both mea-
milliliter of plasma. The intra- and inter-day coefficients of sures were significantly higher during simvastatin monother-
variation for the HMG-CoA reductase activity assay were less apy than during the pretrial control period with enalapril.
than 6%. After administration of amlodipine, both SBP and DBP
tended to decline (p= 0.06 and p= 0.08, respectively). The
blood pressure values during combined treatment with simva-
Data Analysis
statin and amlodipine did not differ from those during the pre-
The pharmacokinetics of simvastatin was characterized by trial control period with enalapril.
the peak concentration (Cmax), the time to Cmax (Tmax), the
elimination half-life (t1/2) and the area under the plasma con-
Discussion
centration-time curve from 0 to infinity [AUC(0−∞)]. The
Cmax and Tmax were obtained directly from the original data. Calcium antagonists and HMG-CoA reductase inhibitors are
The terminal rate constant (ke) used for the extrapolation was often prescribed together for the treatment of hypertension
determined by regression analysis of the log-linear part of the and/or angina pectoris in patients with hypercholesterolemia
concentration-time curve for each subject. The t1/2 was deter- (1, 6, 7). Amlodipine is used with many drugs, such as oral
mined by 0.693/ke. The AUC(0−∞) was calculated by the hypoglycemic drugs, β-blockers, angiotensin-converting
trapezoidal rule for the observed values and subsequent enzyme inhibitors, and so on. However, there have been no
extrapolation to infinity. Data are represented as the reports on the interaction between amlodipine and any other
mean±SD. Data were analyzed by a paired t-test or Wilcoxon drug, with the exception that the interaction of amlodipine
signed-rank test where appropriate. Differences with p values with grapefruit juice was shown to increase the AUC of amlo-
< 0.05 were considered statistically significant. dipine (34). This study is the first to report that amlodipine
affected the plasma concentrations of HMG-CoA reductase
inhibitors.
Results
Simvastatin is hydrolyzed by esterases to simvastatin acid,
No subjects reported a serious clinical, laboratory or other which is an active inhibitor of HMG-CoA reductase (10−12).
adverse effect, and no subjects were discontinued. Simvastatin is extensively metabolized to several oxidative
products by CYP3A4 (10−12). Some of the hydroxyl acid
forms of these products also inhibit HMG-CoA reductase (10,
Pharmacokinetics of Simvastatin HMG-CoA
11). In this study, we measured the total HMG-CoA reductase
Reductase Inhibitor Concentrations
inhibitory activity resulting from simvastatin acid and all
Plasma concentrations of HMG-CoA reductase inhibitors other active acid metabolites of simvastatin, since this level is
226 Hypertens Res Vol. 28, No. 3 (2005)

Table 3. Systolic BP and Diastolic BP during Pretrial Con-

trol Period with Enalapril, Simvastatin Monotherapy and
Combined Treatment with Simvastatin and Amlodipine
Systolic BP Diastolic BP
(mmHg) (mmHg)
Simvastatin+enalapril
(pretrial control period) 135±19 78±13
Simvastatin 152±22* 89±13*
Simvastatin+amlodipine 140±17 81±11
Values are mean±SD. BP, blood pressure. *p<0.05 vs. simva-
statin+enalapril.

administration of simvastatin and diltiazem resulted in a

Fig. 2. Mean levels of serum lipid parameters on the last reduction of TC and LDL-C levels (18). However, we did not
day of 4 weeks of treatment with simvastatin (5 mg/day) or observe such a reduction of TC and LDL-C levels, despite the
combined treatment with simvastatin (5 mg/day) and amlo- fact that amlodipine increased the plasma concentrations of
dipine (5 mg/day). TC, total cholesterol; LDL-C, low-density HMG-CoA reductase inhibitors. The pharmacokinetic inter-
lipoprotein cholesterol; HDL-C, high-density lipoprotein actions observed in the present study, such as the 30%
cholesterol; TG, triglycerides. Each column represents the increase in the AUC of HMG-CoA reductase inhibitors, may
mean ± SD. not have been sufficient to alter the pharmacodynamic
response. Moreover, we cannot exclude the possibility that
the number of patients was not sufficient to detect the phar-
believed to be relevant to the systemic adverse effects for this macodynamic differences. Further investigations will be
class of agents (35). needed to clarify the pharmacodynamic impact of simvastatin
The pharmacokinetics of simvastatin has been shown to be with amlodipine on TC and LDL-C.
affected by potent CYP3A4 inhibitors (13−15, 18). Amlo- In conclusion, this study is the first report of the drug inter-
dipine, which is metabolized by CYP3A4, has been reported action between simvastatin and amlodipine after a long-term
to show inhibitory effects on CYP3A4 in vitro (31). However, treatment. Although amlodipine increases the plasma concen-
the influence of amlodipine on the substrate drugs of trations of HMG-CoA reductase inhibitors, the impact of
CYP3A4 has not been clarified yet. In this study, amlodipine amlodipine on simvastatin is smaller than that of diltiazem.
significantly increases the AUC of HMG-CoA reductase Since these drugs are often used concomitantly for patients
inhibitors after co-administration of simvastatin by 30%. It with hypertension and hypercholesterolemia, amlodipine
has been reported that the AUC of HMG-CoA reductase could be used more safely with simvastatin than diltiazem.
inhibitors was increased 4-fold with itraconazole (13), which
is known to be a potent inhibitor of CYP3A4. Some studies Acknowledgements
have show adverse effects, including rhabdomyolysis, in
patients treated with simvastatin and CYP3A4 inhibitors such The authors are grateful to Dr. Takashi Ishizaki (Teikyo-Heisei
University) for his helpful insights and to H. Kobayashi for tech-
as itraconazole and ketoconazole (8). These reports suggested
nical assistance.
that the co-administration of simvastatin with these inhibitors
enhanced the risk of adverse effects, because of the dose-
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